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PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML
ORAL SUSPENSION & ORAL SUSPENSION SACHETS
PL 12063/0060-1
UKPAR
TABLE OF CONTENTS
Lay Summary
Page 2
Scientific discussion
Page 3
Steps taken for assessment
Page 18
Steps taken after assessment
Page 19
Summary of Product Characteristics
Page 20
Product Information Leaflet
Page 37
Labelling
Page 41
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
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PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML
ORAL SUSPENSION & ORAL SUSPENSION SACHETS
PL 12063/0060-1
LAY SUMMARY
The MHRA granted Wrafton Laboratories Limited Marketing Authorisations (licences) for the
medicinal products Paramed Ibuprofen For Children 100mg/5ml Oral Suspension and Oral
Suspension Sachets (PL 12063/0060-1) on 7th September 2006. These products are to be sold as
a Pharmacy only medicine (PL 12063/0060) which is presented in a bottle and a General Sales
List product (PL 12063/0061) which is presented in a sachet.
Paramed Ibuprofen For Children 100mg/5ml Oral Suspension contain the active ingredient
Ibuprofen.
This application is claiming essential similarity to Junifen suspension 100mg/5ml
(PL 00327/0077). The licence was granted on the 11th August 1993 and was held by Crookes
Healthcare Limited. Junifen suspension 100mg/5ml has been replaced on the market by Nurofen
For Children 100mg/5ml oral suspension (PL 00327/0085) and as such these products can be
used interchangeably.
No new or unexpected safety concerns arose from this abridged application and it was, therefore,
judged that the benefits of taking Paramed Ibuprofen For Children 100mg/5ml Oral Suspension
and Oral Suspension Sachets outweighs the risk, hence a Marketing Authorisation has been
granted.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
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PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML
ORAL SUSPENSION & ORAL SUSPENSION SACHETS
PL 12063/0060-1
SCIENTIFIC DISCUSSION
TABLE OF CONTENTS
Introduction
Page 4
Pharmaceutical assessment
Page 5
Preclinical assessment
Page 12
Clinical assessment
Page 13
Overall conclusions and risk benefit assessment
Page 17
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
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INTRODUCTION
The UK granted a marketing authorisation for the medicinal products Paramed Ibuprofen for
Children 100mg/5ml Oral Suspension and Oral Suspension Sachets (PL 12063/0060-1) to
Wrafton Laboratories Limited on 7th September 2006. The Pharmacy only medicine (PL
12063/0060) is presented in a bottle and the General Sales List product (PL 12063/0061) is
presented in a sachet.
These applications were submitted as abridged applications according to article 10.1 [formerly
Article 10.1(a)(iii)] of Directive 2001/83/EC, cross-referring to Junifen suspension 100mg/5ml
(PL 00327/0077). The licence was granted on the 11th August 1993 and was held by Crookes
Healthcare Limited. Junifen suspension 100mg/5ml has been replaced on the market by Nurofen
For Children 100mg/5ml oral suspension (PL 00327/0085).
This product contains the active ingredient Ibuprofen which is used for the fast and effective
reduction of fever, including post immunisation pyrexia, cold and flu symptoms, and the fast and
effective relief of mild to moderate pain, such as sore throat, teething pain, toothache, earache,
headache, minor aches and sprains.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
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PHARMACEUTICAL ASSESSMENT
Our Reference:
Product:
Marketing Authorisation Holder:
Active Ingredient(s):
Type of Procedure:
Submission Type:
Submission Category:
Submission Complexity:
PL 12063/0060 - 0001
PL 12063/0060 WRAFTON LABS IBUPROFEN
ORAL SUSPENSION 100MG/5ML
WRAFTON LABORATORIES LIMITED
IBUPROFEN.
National
Initial
Abridged
Standard
1. INTRODUCTION
These are abridged applications for Marketing Authorisations in the UK submitted under Article
10.1 [formerly Article 10.1(a)(iii)] of Directive 2001/83/EC, for products claiming essential
similarity to Junifen suspension 100mg/5ml (PL 00327/0077). The licence was granted on the
11th August 1993 and was held by Crookes Healthcare Limited. Junifen suspension 100mg/5ml
has been replaced on the market by Nurofen For Children 100mg/5ml oral suspension (PL
00327/0085). The Nurofen For Children 100mg/5ml oral suspension licence is a standard
abridged application of the cross referenced Junifen suspension 100mg/5ml. Nurofen For
Children 100mg/5ml suspension was used as the medicinal product in the bioequivalence study.
The Pharmacy only medicine (PL 12063/0060) is presented in a bottle and the General Sales List
product (PL 12063/0061) is presented in a sachet.
2.
DRUG SUBSTANCE
2.1
General information
Details of the drug substance supplier have been supplied. A Certificate of Suitability granted
12th February 2001, has been supplied, with permission for use with Ibuprofen products from the
manufacturer.
The re-test date on the certificate of suitability is three years if stored in lock-rim fibre drums.
Certificates of analysis have been provided for batches tested at the manufacturer of the drug
substance.
2.2
Manufacture
2.2.1 Manufacturers
Details of the drug substance manufacturer have been supplied.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
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2.3
Control of drug substance
2.3.1 Specification
The specifications provided for ibuprofen are supplied. These include the requirements of the
European Pharmacopoeia. The specifications are taken from the manufacturer’s certificate of
analysis, which includes the additional requirements of the certificate of suitability.
2.3.2 Container closure system
The material is packed in lock-rim fibre drums.
3.
DRUG PRODUCT
3.1 Composition
The composition of the suspension is summarised in table 2. The suspension is an opaque white
to off-white, orange flavoured viscous suspension. The suspension is packed in a polyethylene
terephthalate (PET) amber coloured bottle containing 100ml or 150ml with a high density
polyethylene child-resistant cap fitted with a polypropylene inner layer and insert comprising
folding boxboard/paper/aluminium foil/wax disc or laminate sachets consisting of Surlyn
Ionomer/low density polyethylene/aluminium paper.
Table 2
Name of Ingredients
Active
Ibuprofen
Excipients
Polysorbate 80
Maltitol liquid
Acesulfame potassium
Sodium cyclamate
Xanthan gum
Glycerol
Sodium benzoate
Disodium edetate
Anhydrous citric acid
Orange flavour F/32297
Purified water
Reference
Ph Eur
Ph Eur
Ph Eur
Ph Eur
Ph Eur
Ph Eur
Ph Eur
Ph Eur
Ph Eur
Ph Eur
In-house spec
Ph Eur
3.2 Pharmaceutical Development
The compatibility of ibuprofen in combination with the excipients has been demonstrated by
cross referral to the finished product stability data, highlighting the fact that there was no
evidence of physical or chemical deterioration within the study. The stability data was also used
to show that the ibuprofen at the selected particle size stays in suspension and produces a
consistent product.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
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The excipients used are frequently used in these types of preparations and are at standard
concentrations. The function of each excipient has been stated with reasons for selection in
preference to suitable alternatives.
There are no overages in the formulation.
3.3
Manufacture
3.3.1
Manufacturer(s)
The manufacturer has been stated.
For the sachets there is also the possibility that sachet filling and sealing can occur at another site
and details of this have been provided.
3.3.2
Batch formula
The batch formulas have been provided. The proposed maximum batch size for production and
the typical batch size have been stated. There is no overage of ingredients used.
3.3.3
Manufacturing process and process controls
A flow diagram detailing the manufacturing process has been provided. A written summary of
the process has also been included for the different batch sizes.
3.3.4
In-process controls
Appropriate in-process controls have been described.
3.3.5
Control of critical steps and intermediates
Appropriate details of critical steps and intermediates have been provided.
3.3.6
Process validation or evaluation
The data presented demonstrates that adequate controls are in place to manufacture the ibuprofen
suspension and fill it into both bottles and sachets in a reproducible fashion at the pilot scale. The
processes used are standard processes for the manufacturer. Consequently, the validation data
provided is sufficient.
3.4
3.4.1
Control of excipients
Specification
Most of the excipients have monographs in the European Pharmacopoeia. A certificate of
analysis from each of the respective raw material manufacturers has been supplied. The
analytical procedures are stated as those detailed in the Pharmacopoeia with adequate validation
being performed. The finished product manufacturer performs limited testing when supplied with
a certificate of analysis or full testing when not supplied with a certificate of analysis. The
methods used are pharmacopoeia methods and as such no validation data has been supplied.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
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3.4.2
Novel excipients
The orange flavour F/32297 is a food grade product compliant with Directive 83/388/EEC. A
partial breakdown of the ingredients is supplied with the in-house specifications and a certificate
of analysis from the supplier. A declaration of conformity with Directive 83/833/EEC and a TSE
declaration have also been supplied.
3.5
3.5.1
Control of drug product
Specification
Finished product specifications for this product have been provided
Ibuprofen suspension has a British Pharmacopoeia specification. The proposed finished product
specification fufils the requirements of the pharmacopoeia specification with an alternative test
being used for identification.
The microbiology testing is performed on every batch at release.
3.5.2
Analytical procedures
In-house methods have been supplied for appearance, odour, viscosity, specific gravity and
weight, pH, identification, taste, assay of sodium benzoate, assay of ibuprofen, assay of 4isobutylacetophenone and dissolution.
The dissolution method is based on the method in the USP.
3.5.3
Validation
The HPLC method for assay of ibuprofen and sodium benzoate has been validated. The method
has precision and accuracy.
The only validation performed in relation to the dissolution method is that relating to the HPLC
analysis of samples.
Acceptable validation data in relation to the microbiology methods used to assess the quality of
the suspension have been provided demonstrating recovery of specified organisms in the
presence of the product.
3.5.4
Batch analyses
Batch analyses of the batches manufactured during validation of the process are provided.
These batches have also been placed on stability. There is reference to the batches of drug
substance used in each batch of Ibuprofen paediatric suspension.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
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3.6
Container closure system
The packaging used for the 100ml or 150ml presentation comprises an amber coloured
polyethylene terephthalate (PET) bottle with child-resistant caps. The caps are high density
polyethylene outers which are lined inside with polypropylene. There is a disc shaped multilayered liner inside the cap which is folding boxboard/paper/aluminium foil/wax with the
aluminium foil/wax as the product contact layer.
The packaging used for the 5ml presentation comprises a laminate sachet of Surlyn ionomer
(contact material)/low density polyethylene/8 micron aluminium/paper.
Both presentations are supplied with a CE marked double-ended spoon with measures of 2.5ml
and 5ml.
The finished product manufacturer tests the bottle and cap for appearance when supplied
accompanied with a suitable certificate of analysis or certificate of conformity.
The sachet is tested for appearance and IR identity when supplied accompanied with a suitable
certificate of analysis or certificate of conformity.
The product was assessed for extractables after contact between the packaging and the product
under extreme conditions. No extractables are shown to interfere with the analysis of ibuprofen,
sodium benzoate or 4-isobutylacetophenone. The packaging materials are in compliance with the
relevant guidelines on migration limits with relevant certification presented.
3.7 Stability
Bottles
Two batches have been put on to stability, with the batches utilising two batches of drug
substance. The storage conditions are 25°C/60%RH (12 months) and 40°C/75%RH (6 months).
The batches were assessed on the basis of the shelf-life specification. Microbiological testing
was performed initially and then at each 6 monthly interval.
The data provided demonstrates that the Ibuprofen paediatric suspension is stable in the 100ml
PET bottles with respect to the physical, chemical and microbiological properties when stored at
25°C/60%RH for 24 months and 40°C/75%RH for 6 months. The stability study is set to
continue at 25°C/60%RH up to 36 months. The influence of time and storage conditions on
sedimentation has not been discussed.
The applicant is proposing a shelf life of 36 months without any special precautions for storage,
with the intention of extending this time when more data becomes available. This is acceptable.
A commitment has been made that the full-scale production batches will go on to stability.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
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Sachets
Two batches have been put on to stability, with the batches utilising two batches of drug
substance. The storage conditions are 25°C/60%RH (12 months), 30°C/60%RH (12 months) and
40°C/75%RH (6 months).
The batches were assessed on the basis of the shelf-life specification. Microbiological testing
was performed initially and then at 6, 9 and 12 months.
The applicant is proposing a shelf life of 24 months with the special precaution for storage of
‘Do not store above 25°C’, with the intention of extending this time when more data becomes
available. This is acceptable.
3.8
Other information
3.8.1 Bioanalytical methods
Validation of the method has been performed. It has been demonstrated that the method is
selective for ibuprofen. The method has also been shown to be precise and accurate.
3.8.2
Bioequivalence
A bioequivalence study was performed. This was a comparative, randomised, single-dose,
crossover study. Comparing the Ibuprofen 100mg/5ml suspension with Nurofen For Children
100mg/5ml suspension in healthy adults. Twenty one subjects were enrolled in the study. Data
was analysed for twenty due to one withdrawal. The batch of Ibuprofen 100mg/5ml suspension
is at least 10% of the proposed maximum batch size.
The confidence intervals derived are within the 80% to 125% acceptance range of the Notes for
Guidance on Bioavailability and Bioequivalence. Ibuprofen 100mg/5ml suspension was
therefore considered to be bioequivalent to Nurofen For Children 100mg/5ml suspension at a
dose of 400mg ibuprofen.
3.8.3
Essential similarity
The dissolution profiles of the Ibuprofen 100mg/5ml suspension are comparable to Nurofen for
Children 100mg/5ml suspension. This has been conducted only on the batches used in the
bioequivalence study.
No discussion on the chemical essential similarity has been presented. It has been demonstrated
that no degradation products are formed on stressed samples of the finished product. The product
is analysed for the appropriate degradant as detailed in the pharmacopoeia monograph and
shown to be compliant. The impurities from the active substance are controlled by the
pharmacopoeia monograph. The control presented and the stability of the product justifies the
omission of a comparison.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
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4.
PRODUCT LITERATURE
4.1
SPC
The SPC is in compliance with the guidelines and quality section.
4.2
PIL
The PIL is in compliance with the SPC and guidelines.
4.3
LABEL
The labels are in compliance with the SPC and guidelines.
5.
ADMINISTRATIVE
5.1
MAA form
The MAA form is in compliance with the SPC and guidelines.
5.2
Quality Overall Summary
The report is a summary of the module and is satisfactory.
6.
CONCLUSIONS AND ADVICE
A marketing authorisation can be granted.
Pharmaceutical Assessor
Original assessment: 27th August 2004
Response assessment: 30th March 2005
Response assessment 10th November 2005
Response assessment: 14th March 2006
Response assessment: 14th June 2006
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
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PRECLINICAL ASSESSMENT
No new preclinical data have been supplied with these applications and none are required for
applications of this type.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
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CLINICAL ASSESSMENT
INTRODUCTION
These are National Abridged generic applications for MA for OTC Ibuprofen Paediatric
Suspension for 100mg/5ml and are submitted under 10.1 [formerly Article 10.1(a)(iii)] of
Directive 2001/83/EC. Essential similarity to Junifen Suspension 100mg/5ml (PL 00327/0077,
Crookes Healthcare Ltd), which was first licensed >10 years ago (Aug 1993) is claimed. The
proposed legal status is P (OTC - pharmacy only). Subsequent MRP is not planned. It is
proposed that Ibuprofen Paediatric Suspension (PL 12063/0060) be on sale in pharmacies only
(P legal status) and Ibuprofen Paediatric Suspenson or Ibuprofen Suspension for Children (PL
12063/0061) be on general sale (legal status GSL).
Preparations containing ibuprofen have been available in the UK since 1966 and the Clinical
Summary reviews the use of ibuprofen in children. The application is supported by a single
bioequivalence study (vs. Nurofen for Children 100mg/5ml).This documentation for this study
was supplied with Module 3; no Module 5 was submitted.
The Clinical Expert is appropriately medically qualified.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Introduction
The PK of ibuprofen is well understood and has been reviewed in the Clinical Summary.
In support of this generic application, a single bioequivalence study has been conducted to prove
that the proposed ibuprofen suspension 100mg/5ml (Wrafton Laboratories Ltd) and Nurofen for
Children (Crookes Healthcare; PL 00327/0085). The batch of Ibuprofen 100mg/5ml suspension
is at least 10% of the proposed maximum batch size.
Methods
Study SC00403 Title: A single-dose, randomised, crossover study to compare the absorption of
two formulations of ibuprofen suspension in healthy male and female volunteers
The objective of this study was to evaluate the PK characteristics and relative bioavailability
profile of the proposed ibupfrofen siuspension (Wrafton Laboratories Ltd)- Test product compared to the UK licensed comparator Nurofen for Children (Crookes Healthcare Ltd; PL
00327/0085) – reference product.
The study was carried-out in 21 healthy male and female adult volunteers (20 of whom
completed the study). As the PK of ibuprofen is independent of age in the proposed dose range,
extrapolation from findings in adults is accepted.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
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The dose given was 400mg/20ml. Samples were taken predose (0 hours) and 0.25, 0.5, 0.75, 1,
1.5, 2, 3, 5, 7, 9 and 12 hours post dose. An adequate period of at least 48 hours was used
between treatments.
•
Analytical methods
The methods used were satisfactory.
•
Pharmacokinetic data analysis
The primary parameters were Cmax, AUC0-t and extrapolated AUC0-∞. Secondary parameters
were tmax, t½, MRT (mean residence time – extrapolated area under the concentration vs. time
curve) and kel (terminal elimination rate constant). Safety was also monitored using standard
methodology.
•
Statistical analysis
PK parameters were determined in a model-independent way. ANOVA and 90% CIs were
calculated for the mean ratios of AUC and Cmax after log transformation. Parametric testing was
used when data were normally distributed; non-parametric testing when not normally distributed.
A comparison of tmax was done through descriptive statistics. The acceptance range for the
90%C is to establish bioequivalence of Test: Reference formulations was the standard 80-125%,
using log transformed data of the primary endpoints, as per the CPMP Guideline.
Bioequivalence was determined using the 90% confidence interval of the relative mean AUC 0-t,
AUC∞ and Cmax of the test to reference formulation which should be 80% to 125%. The results
are presented in section II.1.3, which follows.
Absorption
•
Bioequivalence
The mean tmax values for Ibuprofen 100mg/5ml suspension (Test product) and Nurofen for
Children 100mg/5ml suspension (Reference product) were 1.10 and 0.86 hours respectively. The
results for the primary parameters are tabulated in Tables 1and 2.
Table I. Summary statistics for the primary parameters Test vs Reference
Variable
Cmax (µg/ml)
AUC0-t
(µg/ml.h)
AUC0-∞
(µg/ml.h)
Arithmetic mean
Test
Reference
37.80
38.96
± 7.18
± 7.13
120.42
117.23
± 25.31
± 20.17
123.49
119.92
± 26.67
± 20.82
Test
18.88
Minimum
Reference
26.01
Test
49.46
maximum
Reference
52.72
72.38
78.73
195.68
163.34
74.76
80.28
205.16
166.17
Table 2. CIs and point estimates for the primary parameters Test vs Ref
Variable
Cmax (µg/ml)
AUC0-t
(µg/ml.h)
AUC0-∞
(µg/ml.h)
Geometric mean
Test
Reference
37.06
38.32
118.04
115.51
90% CI
Point estimate
91.40%-102.30%
96.64%-108.50%
96.70%
102.19%
120.96
96.97%-108.13%
102.40%
118.13
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
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As can be seen from the tables, Study SC00403 showed that for the test suspension (ibuprofen
suspension, Wrafton Laboratories) and the reference suspension (Nurofen for Children, Crookes)
were as follows:
• Mean Cmax for the Test suspension was 38.32 µg/ml and for the Reference suspension
was 38.32µg/ml (point estimate 96.7% and 90% CIs 91.4 – 102.3%).
• Mean AUC0-t was 118.04µg/ml.h for the Test suspension cf. 115.51µg/ml.h for the
rReference (point estimate 102.19%; 90% CIs 96.64-108.50%).
• Mean extrapolated AUC0-∞ was 120.96µg/ml.h for the test and 118.13µg/ml.h for the
Reference product (point estimate 102.40%; 90% CI 96.97 – 108.13%).
These results are well within the acceptance criteria and the products may, therefore, be
considered bioequivalent. Comparison of the additional parameters revealed the following:
• The median (Min-Max) tax values for Test and Reference products were 0.75h (0.5-3.0h)
and 0.75h (0.50-2.0h), respectively. The statistically significant treatment effect
(p=0.0324) was observed, indicating a longer tmax for the Test product.
• The geometric means calculated for t½ were 2.22h and 2.06h, respectively for Test and
Reference products.
• The geometric means calculated for MRT were 3.30h and 3.13h, respectively for the Test
and Reference products. A low intra-individual CV of 7.04% resulted in a small least
significant difference value and consequently the statistically significant treatment effect
(0.0266) was observed, indicating a longer MRT for the Test product.
Assessor’s overall conclusions on pharmacokinetics
Study SC00403 has estabished that the rate and extent of absorption of ibuprofen from the
proposed formulation is bioequivalent to that of the reference product, Nurofen for Children.
Although the study was conducted in adults, a study in children would not be ethical given that
there is no reason to believe the data cannot be extrapolated from adults to the target population.
The Applicant compared the proposed formulation with Nurofen, presumably as this is the
market leader and Junifen, with which essential similarity is claimed, is no longer marketed. The
Assessor has discussed this with the pharmaceutical assessor and unit manager and this approach
is considered to be satisfactory from a regulatory perspective.
Pharmacodynamics
ATC Code M01AE –propionic acid derivatives.
The PD actions of ibuprofen in both adults and children are well understood. No new data have
been submitted and none are required for this type of application.
CLINICAL EFFICACY
No new data have been submitted and none are required for this type of application. The efficacy
of ibuprofen in the proposed indications is well-recognised and has been adequately reviewed in
the Clinical Summary.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
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CLINICAL SAFETY
No new data have been submitted and none are required for this type of application. The safety
profile of ibuprofen in both adults and children is well established and has been reviewed in the
Clinical Summary. There are no new safety concerns arising from this review or from the Phase I
Bioequivalence study. In this study 6 AEs were reported in 4 volunteers – three reports of
headache, one of vomiting, one of dizziness and one of urticaria. These are consistent with
events seem in Phase I studies and no formulation events can be deduced from these results.
There were no SAEs or other safety findings.
SPC/PIL/Label
Satisfactory.
CONCLUSIONS
Given the demonstration of bioequivalence with Nurofen for Children, the current brand leader
(Junifen being no longer marketed) MA may be granted.
Medical Assessor
October 2004
Updated 2006
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT
QUALITY
The important quality characteristics of Paramed Ibuprofen For Children 100mg/5ml Oral
Suspension and Oral Suspension Sachets (PL 12063/0060-1) are well defined and controlled.
The specifications and batch analytical results indicate consistency from batch to batch. There
are no outstanding quality issues that would have a negative impact on the benefit/risk balance.
PRECLINICAL
No new preclinical data have been supplied with these applications and none are required for
applications of this type.
EFFICACY
Bioequivalence has been demonstrated between the applicant’s Paramed Ibuprofen For Children
100mg/5ml Oral Suspension and Oral Suspension Sachets (PL 12063/0060-1) and the originator
product Junifen suspension 100mg/5ml (PL 00327/0077).
No new or unexpected safety concerns arise from these applications.
The SPC, PIL and labelling are satisfactory and consistent with that for Junifen suspension
100mg/5ml (PL 00327/0077).
RISK BENEFIT ASSESSMENT
The quality of the products is acceptable and no new preclinical or clinical safety concerns have
been identified. The data supplied supports the claim that the applicant’s products and the
innovator products are interchangeable. Clinical experience with Ibuprofen is considered to have
demonstrated the therapeutic value of the compound. The risk benefit is therefore considered to
be positive.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
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PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML
ORAL SUSPENSION & ORAL SUSPENSION SACHETS
PL 12063/0060-1
STEPS TAKEN FOR ASSESSMENT
1
The MHRA received the marketing authorisation application on 27/02/2004
2
Following standard checks and communication with the applicant the MHRA
considered the application valid on 12/03/2004
3
Following assessment of the application the MHRA requested further
information relating to the dossier on 23/08/2004, 14/10/2004, 02/11/2004,
17/06/2004, 07/12/2005 and 14/03/2006
4
The applicant responded to the MHRA’s requests, providing further information
relating to the dossier on 26/08/2004, 18/03/2004, 12/10/2005, 13/02/2006,
14/02/2006, 05/05/2006, 12/05/2006 and 12/06/2006,
5
The application was determined on 07/09/2006
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
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PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML
ORAL SUSPENSION & ORAL SUSPENSION SACHETS
PL 12063/0060-1
STEPS TAKEN AFTER ASSESSMENT
Date
Application
submitted type
Scope
Outcome
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
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PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION
PL 12063/0060
SUMMARY OF PRODUCT CHARACTERISTICS
1.
NAME OF THE MEDICINAL PRODUCT
Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Active Ingredient: Ibuprofen 100 mg/5 ml (equivalent to 2.0% w/v).
This product also contains the excipient maltitol liquid, see section 4.3.
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Oral suspension
Opaque, white to off-white viscous suspension
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
For the fast and effective reduction of fever, including post immunisation pyrexia, cold
and flu symptoms, and the fast and effective relief of mild to moderate pain, such as
sore throat, teething pain, toothache, earache, headache, minor aches and sprains.
4.2
Posology and method of administration
For oral administration and short term use only
Shake the bottle well before use.
For pain and fever:
For children weighing 5 kg or more, the daily dosage of the suspension is 20 mg/kg
bodyweight in divided doses. Using the spoon provided this can be achieved as
follows:
Infants 3 – 6 months (weighing over 5 kg): One 2.5 ml dose may be taken 3 times in 24
hours.
Infants 6 – 12 months: One 2.5 ml dose may be taken 3 to 4 times in 24 hours.
Children 1 – 3 years: One 5 ml dose may be taken 3 times in 24 hours.
Children 4 – 6 years: 7.5 ml dose (5 ml + 2.5 ml spoonful) may be taken 3 times in 24
hours.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 20 -
Children 7 – 9 years: 10 ml dose. Two 5 ml spoonfuls may be taken 3 times in 24
hours.
Children 10 – 12 years: 15 ml dose. Three 5 ml spoonfuls may be taken 3 times in 24
hours.
Not suitable for children under 3 months of age, or for children weighing less than 5 kg,
unless advised by your doctor.
Leave at least 4 hours between doses.
For post immunisation pyrexia:
One 2.5 ml dose followed by one further 2.5 ml dose 6 hours later if necessary. No
more than two 2.5 ml doses in 24 hours. If the fever is not reduced, consult your doctor.
4.3
Contraindications
Hypersensitivity to ibuprofen or any of the constituents of the product
Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis,
angioedema, or urticaria) associated with aspirin or other non-steroidal antiinflammatory drugs.
Patients with a history of, or existing peptic ulceration
History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs
therapy.
Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (see
Section 4.5 Interaction with other medicinal products and other forms of interaction).
Severe hepatic failure, renal failure or heart failure (see Section 4.4 Special warnings
and precautions for use)
Last trimester of pregnancy (see Section 4.6 Pregnancy and lactation)
Each 5 ml spoonful contains 2 g of maltitol liquid. Patients with rare hereditary
problems of fructose intolerance should not take this medicine.
4.4
Special warnings and precautions for use
Bronchospasm may be precipitated in patients suffering from or with a previous history
of bronchial asthma or allergic disease.
Undesirable effects may be minimised by using the minimum effective dose
for the shortest possible duration.
The elderly are at increased risk of the serious consequences of adverse reactions.
Systemic lupus erythematosus and mixed connective tissue disease - increased risk of
aseptic meningitis (See section 4.8 Undesirable effects).
Chronic inflammatory intestinal disease (ulcerative colitis, Crohn’s disease) – as these
conditions may be exacerbated (See section 4.8 Undesirable effects).
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 21 -
Hypertension and/or cardiac impairment as renal function may deteriorate and/or fluid
retention occur.
Renal impairment as renal function may further deteriorate (See section 4.3
Contraindications and Section 4.8 Undesirable effects).
Hepatic dysfunction (See section 4.3 contraindications and Section 4.8 undesirable
effects).
There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin
synthesis may cause impairment of female fertility by an effect on ovulation. This is
reversible upon withdrawal of treatment.
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been
reported with all NSAIDs at anytime during treatment, with or without warning
symptoms or a previous history of serious gastrointestinal events.
Patients with a history of gastrointestinal toxicity, particularly when elderly, should
report any unusual abdominal symptoms (especially gastrointestinal bleeding)
particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications which could
increase the risk of gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants
such as warfarin or anti-platelet agents such as aspirin (See section 4.5 interaction with
other medicinal products and other forms of interaction).
When gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, the
treatment should be withdrawn.
The label will include:
Please read the enclosed leaflet carefully.
Do not let your child take this medicine if they:
•
•
•
•
•
are under 3 months old, or weigh less than 5 kg, unless advised by your doctor
are allergic to ibuprofen or any of the other ingredients, aspirin or other related
painkillers
have or have ever had a stomach ulcer, perforation or bleeding
are intolerant to some sugars
are taking other NSAID painkillers, or aspirin, with a daily dose above 75 mg.
Consult your doctor or pharmacist if your child has asthma, or heart, liver, kidney or
bowel problems, or is receiving any other regular treatment.
Pregnant women considering taking this medicinal product should consult their doctor
before use.
If the child’s symptoms persist for more than 3 days, or worsen consult your doctor.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 22 -
For children under 6 months, if the symptoms persist for more than 24 hours (3 doses)
or worsen, consult your doctor.
Warning – Do not exceed the stated dose.
Keep all medicines out of the reach and sight of children.
Not suitable for children under 3 months of age or weighing less than 5 kg, unless
advised by your doctor.
4.5
Interaction with other medicinal products and other forms of interaction
Ibuprofen should not be used in combination with:
Aspirin:
Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this
may increase the risk of adverse reactions (See section 4.3 Contraindications)
Other NSAIDS:
As these may increase the risk of adverse effects (See section 4.3 Contraindications)
Ibuprofen should be used with caution in combination with:
Anticoagulants:
NSAIDS may enhance the effects of anti-coagulants, such as warfarin (See section 4.4
Special warnings and precautions for use).
Antihypertensives and diuretics:
NSAIDs may diminish the effect of these drugs.
Corticosteroids:
May increase the risk of adverse reactions in the gastrointestinal tract (See section 4.4)
Lithium:
There is evidence for potential increases in plasma levels of lithium.
Methotrexate:
There is a potential for an increase in plasma methotrexate.
Zidovudine:
There is evidence of an increased risk of haemarthroses and haematoma in HIV (+)
haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
4.6
Pregnancy and lactation
Children under 12 are unlikely to become pregnant or breast feed, however, whilst no
teratogenic effects have been demonstrated in animal studies, the use of the suspension
should be avoided if possible during the first six months of pregnancy.
During the third trimester, ibuprofen is contraindicated as there is a risk of premature
closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension.
The onset of labour may be delayed and duration of labour increased with an increased
bleeding tendency in both mother and child (see Section 4.3 – contraindications).
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 23 -
In limited studies, ibuprofen appears in breast milk in very low concentration and is
unlikely to affect the breast fed infant adversely.
See Section 4.4 regarding female fertility.
4.7
Effects on ability to drive and use machines
None expected at recommended doses and duration of therapy.
4.8
Undesirable effects
Hypersensitivity reactions have been reported and these may consist of:
(a) Non-specific allergic reactions and anaphylaxis
(b) Respiratory tract reactivity, eg asthma, aggravated asthma, bronchospasm, dyspnoea
(c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely
exfoliative and bullous dermatoses (including epidermal necrolysis and erythema
multiforme)
The following list of adverse effects relates to those experienced with ibuprofen at OTC
doses, for short-term use. In the treatment of chronic conditions, under long-term
treatment, additional adverse effects may occur.
Hypersensitivity reactions:
Uncommon:
Hypersensitivity reactions with urticaria and pruritus
Very rare:
Severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal
swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe
shock).
Exacerbation of asthma and bronchospasm
Gastrointestinal:
Uncommon:
Abdominal pain, nausea and dyspepsia
Rare:
Diarrhoea, flatulence, constipation and vomiting
Very rare:
Peptic ulcer, perforation or gastrointestinal haemorrhage, sometimes fatal, particularly
in the elderly. Exacerbation of ulcerative colitis and Crohn’s disease (See section 4.4)
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 24 -
Nervous System:
Uncommon:
Headache
Renal:
Very rare:
Acute renal failure, papillary necrosis, especially in long-term use, associated with
increased serum urea and oedema.
Hepatic:
Very rare:
Liver disorders
Haematological:
Very rare:
Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia,
agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like
symptoms, severe exhaustion, unexplained bleeding and bruising.
Skin:
Uncommon:
Various skin rashes
Very rare:
Severe forms of skin reactions such as erythema multiforme and epidermal necrolysis
can occur.
Immune System:
In patients with existing auto-immune disorders (such as systemic lupus erythematosus,
mixed connective tissue disease) during treatment with ibuprofen, single cases of
symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or
disorientation have been observed (See section 4.4).
4.9
Overdose
In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose
response effect is less clear cut. The half-life in overdose is 1.5 – 3 hours.
Symptoms
Most patients who have ingested clinically important amounts of NSAIDs will develop
no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus,
headache and gastrointestinal bleeding are also possible. In more serious poisoning,
toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally
excitation and disorientation or coma. Occasionally patients develop convulsions. In
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 25 -
serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be
prolonged, probably due to interference with the actions of circulating clotting factors.
Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in
asthmatics.
Management
Management should be symptomatic and supportive and include the maintenance of a
clear airway and monitoring of cardiac and vital signs until stable. Consider oral
administration of activated charcoal if the patient presents within 1 hour of ingestion of
a potentially toxic amount. If frequent or prolonged, convulsions should be treated with
intravenous diazepam or lorazepam. Give bronchodilators for asthma.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Propionic acid derivatives
ATC code: M01AE01
Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by
inhibition of prostaglandin synthesis.
It has analgesic, antipyretic and antiinflammatory properties.
Furthermore, ibuprofen reversibly inhibits platelet aggregation.
Ibuprofen has been shown to have an onset of both analgesic and antipyretic action
within 30 minutes.
5.2
Pharmacokinetic properties
Ibuprofen is rapidly absorbed following administration and is rapidly distributed
throughout the whole body. The excretion is both rapid and complete via the kidneys.
Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an
empty stomach. When taken with food, peak levels are observed after 1 – 2 hours.
These times may vary with different dosage forms.
The half life of ibuprofen is about two hours.
In limited studies, ibuprofen appears in the breast milk in very low concentrations.
5.3
Preclinical safety data
There are no preclinical safety data of relevance to the consumer.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 26 -
6.
6.1
PHARMACEUTICAL PARTICULARS
List of excipients
Maltitol Liquid
Glycerol
Xanthan Gum
Sodium Benzoate
Sodium Cyclamate
Citric Acid
Orange Flavour
Acesulfame Potassium
Polysorbate 80
Disodium Edetate
Purified Water
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
3 years.
6.4
Special precautions for storage
There are no special storage instructions.
6.5
Nature and contents of container
Amber-coloured polyethylene terephthalate (PET) bottle with a child-resistant, highdensity polyethylene closure fitted with a polypropylene inner layer and insert
comprising folding boxboard/paper/aluminium foil/wax disc. The bottle contains 100
ml of product. A double-ended spoon with measures of 2.5 ml and 5 ml is provided.
6.6
Special precautions for disposal
No special requirements.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 27 -
7.
MARKETING AUTHORISATION HOLDER
Wrafton Laboratories Limited
Wrafton
Braunton
North Devon
EX33 2DL
8.
MARKETING AUTHORISATION NUMBER(S)
PL 12063/0060.
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
07/09/2006
10
DATE OF REVISION OF THE TEXT
07/09/2006
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 28 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION
PL 12063/0061
SUMMARY OF PRODUCT CHARACTERISTICS
1.
NAME OF THE MEDICINAL PRODUCT
Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension Sachets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Active Ingredient: Ibuprofen 100 mg/5 ml (equivalent to 2.0% w/v).
This product also contains the excipient maltitol liquid, see section 4.3.
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Oral suspension
Opaque, white to off-white viscous suspension
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
For the fast and effective reduction of fever, including post immunisation pyrexia, cold
and flu symptoms, and the fast and effective relief of mild to moderate pain, such as sore
throat, teething pain, toothache, headache, minor aches and sprains.
4.2
Posology and method of administration
For oral administration and short term use only
Squeeze the sachet to aid mixing.
For pain and fever:
For children weighing 5 kg or more, the daily dosage of the suspension is 20 mg/kg
bodyweight in divided doses. Using the spoon provided this can be achieved as follows:
Infants 3 – 6 months (weighing over 5 kg): One 2.5 ml dose may be taken 3 times in 24
hours.
Infants 6 – 12 months: One 2.5 ml dose may be taken 3 to 4 times in 24 hours.
Children 1 – 3 years: One 5 ml dose may be taken 3 times in 24 hours.
Children 4 – 6 years: 7.5 ml dose (5 ml + 2.5 ml spoonful) may be taken 3 times in 24
hours.
Children 7 – 12 years: 10 ml dose Two 5 ml spoonfuls may be taken 3 times in 24 hours.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 29 -
Not suitable for children under 3 months of age or for children weighing less than 5 kg.
Leave at least 4 hours between doses.
For post immunisation pyrexia:
One 2.5 ml dose followed by one further 2.5 ml dose 6 hours later if necessary. No more
than two 2.5 ml doses in 24 hours. If the fever is not reduced, consult your doctor.
4.3
Contraindications
Hypersensitivity to ibuprofen or any of the constituents of the product
Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis,
angioedema, or urticaria) associated with aspirin or other non-steroidal anti-inflammatory
drugs.
Patients with a history of, or existing peptic ulceration
History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs
therapy.
Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (See
Section 4.5 Interaction with other medicinal products and other forms of interaction).
Severe hepatic failure, renal failure or heart failure (See Section 4.4 Special warnings and
precautions for use)
Last trimester of pregnancy (See Section 4.6 Pregnancy and lactation)
Each 5ml spoonful contains 2g of maltitol liquid. Patients with rare hereditary problems of
fructose intolerance should not take this medicine.
4.4
Special warnings and precautions for use
Bronchospasm may be precipitated in patients suffering from or with a previous history of
bronchial asthma or allergic disease.
Undesirable effects may be minimised by using the minimum effective dose for the
shortest possible duration.
The elderly are at increased risk of the serious consequences of adverse reactions.
Systemic lupus erythematosus and mixed connective tissue disease – increased risk of
aseptic meningitis (See Section 4.8 Undesirable effects).
Chronic inflammatory intestinal disease (ulcerative colitis, Crohn’s disease) – as these
conditions may be exacerbated (See Section 4.8 Undesirable effects).
Hypertension and/or cardiac impairment as renal function may deteriorate and/or fluid
retention occur.
Renal impairment as renal function may further deteriorate (See Section 4.3
Contraindications and Section 4.8 Undesirable effects).
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 30 -
Hepatic dysfunction (See Section 4.3 contraindications and Section 4.8 undesirable effects)
There is limited evidence that drugs which inhibit cyclo-oxygenase/prostaglandin synthesis
may cause impairment of female fertility by an effect on ovulation. This is reversible upon
withdrawal of treatment.
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported
with all NSAIDs at anytime during treatment, with or without warning symptoms or a
previous history of serious gastrointestinal events.
Patients with a history of gastrointestinal toxicity, particularly when elderly, should report
any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the
initial stages of treatment.
Caution should be advised in patients receiving concomitant medications which could
increase the risk of gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants
such as warfarin or anti-platelet agents such as aspirin (See Section 4.5 interaction with
other medicinal products and other forms of interaction).
When gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, the
treatment should be withdrawn.
The label will include:
Please read the enclosed leaflet carefully.
Do not let your child take this medicine if they:
• are under 3 months old, or weigh less than 5 kg
• are allergic to ibuprofen or any of the other ingredients, aspirin or other related
painkillers
• have or have ever had a stomach ulcer, perforation or bleeding
• are intolerant to some sugars
• are taking other NSAID painkillers, or aspirin, with a daily dose above 75 mg
Consult your doctor or pharmacist if your child has asthma, or heart, liver, kidney or bowel
problems, or is receiving any regular treatment.
Pregnant women considering taking this medicinal product should consult their doctor
before use.
If the child’s symptoms persist for more than 3 days or worsen, consult your doctor.
For children under 6 months, if the symptoms persist for more than 24 hours (3 doses) or
worsen, consult your doctor.
Warning – Do not exceed the stated dose.
Keep all medicines out of the reach and sight of children.
Not suitable for children under 3 months of age or weighing less than 5 kg.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 31 -
4.5
Interaction with other medicinal products and other forms of interaction
Ibuprofen should not be used in combination with:
Aspirin:
Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may
increase the risk of adverse reactions (See Section 4.3 contraindications)
Other NSAIDS:
As these may increase the risk of adverse effects (See Section 4.3 contraindications)
Ibuprofen should be used with caution in combination with:
Anticoagulants:
NSAIDS may enhance the effects of anti-coagulants, such as warfarin (See Section 4.4
special warnings and precautions for use).
Antihypertensives and diuretics:
NSAIDs may diminish the effect of these drugs.
Corticosteroids:
May increase the risk of adverse reactions in the gastrointestinal tract (See Section 4.4)
Lithium:
There is evidence for potential increases in plasma levels of lithium.
Methotrexate:
There is a potential for an increase in plasma methotrexate.
Zidovudine:
There is evidence of an increased risk of haemarthroses and haematoma in HIV (+)
haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
4.6
Pregnancy and lactation
Children under 12 are unlikely to become pregnant or breast feed, however, whilst no
teratogenic effects have been demonstrated in animal studies, the use of the suspension
should be avoided if possible during the first six months of pregnancy.
During the third trimester, ibuprofen is contraindicated as there is a risk of premature
closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension.
The onset of labour may be delayed and the duration increased with an increased bleeding
tendency in both mother and child. (See section 4.3 contraindications).
In limited studies, ibuprofen appears in the breast milk in very low concentration and is
unlikely to affect the breast-fed infant adversely.
See Section 4.4 regarding female fertility.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 32 -
4.7
Effects on ability to drive and use machines
None expected at recommended doses and duration of therapy.
4.8
Undesirable effects
Hypersensitivity reactions have been reported and these may consist of:
(a) Non-specific allergic reactions and anaphylaxis
(b) Respiratory tract reactivity, eg asthma, aggravated asthma, bronchospasm, dyspnoea
(c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative
and bullous dermatoses (including epidermal necrolysis and erythema multiforme)
The following list of adverse effects relates to those experienced with ibuprofen at OTC
doses, for short-term use. In the treatment of chronic conditions, under long-term
treatment, additional adverse effects may occur.
Hypersensitivity reactions:
Uncommon:
Hypersensitivity reactions with urticaria and pruritus
Very rare:
Severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal
swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).
Exacerbation of asthma and bronchospasm
Gastrointestinal:
Uncommon:
Abdominal pain, nausea and dyspepsia
Rare:
Diarrhoea, flatulence, constipation and vomiting
Very rare:
Peptic ulcer, perforation or gastrointestinal haemorrhage, sometimes fatal, particularly in
the elderly. Exacerbation of ulcerative colitis and Crohn’s disease (See section 4.4)
Nervous System:
Uncommon:
Headache
Renal:
Very rare:
Acute renal failure, papillary necrosis, especially in long-term use, associated with
increased serum urea and oedema.
Hepatic:
Very rare:
Liver disorders
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 33 -
Haematological:
Very rare:
Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia,
agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like
symptoms, severe exhaustion, unexplained bleeding and bruising.
Skin:
Uncommon:
Various skin rashes
Very rare:
Severe forms of skin reactions such as erythema multiforme and epidermal necrolysis can
occur.
Immune System:
In patients with existing auto-immune disorders (such as systemic lupus erythematosus,
mixed connective tissue disease) during treatment with ibuprofen, single cases of
symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or
disorientation have been observed (See section 4.4).
4.9
Overdose
In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose
response effect is less clear cut. The half-life in overdose is 1.5 – 3 hours.
Symptoms
Most patients who have ingested clinically important amounts of NSAIDs will develop no
more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache
and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen
in the central nervous system, manifesting as drowsiness, occasionally excitation and
disorientation or coma. Occasionally patients develop convulsions. In serious poisoning
metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably
due to interference with the actions of circulating clotting factors. Acute renal failure and
liver damage may occur. Exacerbation of asthma is possible in asthmatics.
Management
Management should be symptomatic and supportive and include the maintenance of a clear
airway and monitoring of cardiac and vital signs until stable. Consider oral administration
of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic
amount. If frequent or prolonged, convulsions should be treated with intravenous
diazepam or lorazepam. Give bronchodilators for asthma.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Propionic acid derivatives
ATC code: M01AE01
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 34 -
Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by
inhibition of prostaglandin synthesis. It has analgesic, antipyretic and anti-inflammatory
properties.
Furthermore, ibuprofen reversibly inhibits platelet aggregation.
Ibuprofen has been shown to have an onset of both analgesic and antipyretic action within
30 minutes.
5.2
Pharmacokinetic properties
Ibuprofen is rapidly absorbed following administration and is rapidly distributed
throughout the whole body. The excretion is both rapid and complete via the kidneys.
Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an
empty stomach. When taken with food, peak levels are observed after 1 – 2 hours. These
times may vary with different dosage forms.
The half life of ibuprofen is about two hours.
In limited studies, ibuprofen appears in the breast milk in very low concentrations.
5.3
Preclinical safety data
There are no preclinical safety data of relevance to the consumer.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Maltitol Liquid
Glycerol
Xanthan Gum
Sodium Benzoate
Sodium Cyclamate
Citric Acid
Orange Flavour
Acesulfame Potassium
Polysorbate 80
Disodium Edetate
Purified Water
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
2 years.
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 35 -
6.4
Special precautions for storage
Do not store above 25°C.
6.5
Nature and contents of container
The suspension is packed in laminate sachets consisting of Surlyn® ionomer (product
contact material)/low density polyethylene/8 micron aluminium/paper.
Each sachet contains 5 ml of the suspension.
Pack sizes of 8 or 16 sachets in a cardboard carton.
A double-ended spoon with measures of 2.5 ml and 5 ml is provided.
6.6
Special precautions for disposal
No special requirements.
7.
MARKETING AUTHORISATION HOLDER
Wrafton Laboratories Limited
Wrafton
Braunton
North Devon
EX33 2DL
8.
MARKETING AUTHORISATION NUMBER(S)
PL 12063/0061.
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
07/09/2006
10
DATE OF REVISION OF THE TEXT
07/09/2006
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 36 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION
PL 12063/0060
PRODUCT INFORMATION LEAFLET
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 37 -
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 38 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION SACHETS
PL 12063/0061
PRODUCT INFORMATION LEAFLET
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 39 -
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 40 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION
PL 12063/0060
LABEL
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 41 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION
PL 12063/0060
LABEL
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 42 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION
PL 12063/0060
LABEL
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 43 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION SACHETS
PL 12063/0061
LABEL
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 44 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION SACHETS
PL 12063/0061
LABEL
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 45 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION SACHETS
PL 12063/0061
LABEL
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 46 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION SACHETS
PL 12063/0061
LABEL
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 47 -
PARAMED IBUPROFEN FOR CHILDREN 100 MG/5 ML ORAL SUSPENSION SACHETS
PL 12063/0061
LABEL
MHRA PAR Paramed Ibuprofen for Children 100 mg/5 ml Oral Suspension & Oral
Suspension Sachets PL 12063/0060-1
- 48 -